New single-cell study offers fresh perspectives on gastric cancer

During the advancement of gastric cancer, a new study headed by scientists at The University of Texas MD Anderson Cancer Centre offers a better knowledge of the evolution of the tumour microenvironment. A new treatment target and a connection between multicellular communities and clinical outcomes are two of the study's standout findings published today in Cancer Cell.

Due to its intrinsic resistance to therapy, gastric adenocarcinoma is one of the most deadly malignancies in the world, yet little is known about the cellular and molecular processes that lead from early pre-cancer to tumour growth and dissemination. This study clarifies how different immune and stromal cell subsets change as stomach cancer develops.

The study was conducted by Linghua Wang, M.D., Ph.D., associate professor of Genomic Medicine, in collaboration with Jaffer Ajani, M.D., professor of Gastrointestinal Medical Oncology, and Ruiping Wang, Ph.D., postdoctoral fellow in the Wang Lab.

"Gastric adenocarcinoma exhibits a high degree of heterogeneity with respect to both its phenotypes and molecular characteristics, but research around it has lagged behind other cancer types," Wang said. "Most studies have concentrated on tumor cells and largely overlooked the immune and stromal cells within the tumour microenvironment, which are very dynamic and play critical roles in cancer progression. This study represents the largest single-cell RNA sequencing cohort of gastric adenocarcinoma to date and brings important new insights into how these cell populations impact disease progression."

By obtaining single-cell RNA sequencing (scRNA-seq) data from 68 gastric adenocarcinoma samples encompassing various disease stages -- including precancerous lesions, localized tumours and distant metastases -- along with normal tissue and peripheral blood samples, the team characterized the diverse immune and stromal cell populations within the tumour microenvironment and discovered exploitable targets to modulate the tumour microenvironment.

A novel approach allows researchers to dissect the complex tumour microenvironment. Various immune and stromal cell subsets formed multicellular communities, or collections of cell states, present in the tumour microenvironment of an individual tumour sample. The research team termed these groups "ecotypes" and identified six unique ecotypes, with each dominated by specific immune and stromal cell states.

"While many published single-cell studies have focused on characterizing the heterogeneity of each individual cell compartment, our study utilized a novel approach and concept of integrating various components of the tumour microenvironment to define ecotypes and investigated their clinical significance," Wang said. "This approach can readily be applied to studies in other cancer types."

A notable discovery is that two ecotypes (EC3 and EC6) correlated with different histological, genomic and clinical features of primary gastric adenocarcinomas. Tumours categorized as EC3 were composed mainly of immune cell subsets, whereas EC6 tumours predominantly included stromal cell subsets. Patients with EC6 tumours had a more aggressive disease and significantly shorter survival compared to those with EC3 tumours.

Findings point to SDC2 as potential therapeutic target in stromal cells

While stromal components within the tumour microenvironment play crucial roles in tumour initiation, progression and metastases, cancer treatment strategies have thus far rarely focused on modulating stromal components, especially in patients with gastric adenocarcinoma.

This study identified SDC2 as a potential target worthy of further investigation. Researchers found SDC2 overexpression in stromal cells, especially in cancer-associated fibroblasts, was correlated with aggressive disease and advanced stages, and strongly associated with unfavorable survival outcomes. In addition, SDC2 expression was consistently elevated in stromal cells across various other cancer types, including pancreatic cancer, colorectal cancer, bladder cancer, breast cancer and clear cell renal cell carcinoma.

"There are unmet needs for patients with gastric adenocarcinoma every step of the way in their clinical journey," Ajani said. "Our team strives to use novel interrogations to discover new therapeutic targets to improve the outcomes of these patients. While there are many questions left to answer, targeting SDC2 in cancer-associated fibroblasts represents a potentially exciting avenue that warrants further investigation."